Elucidating the impact of APP in DS pathogenesis using stem cell models

Griffiths R1, Fortuna P1, Ovchinnikov D1, Balachandran A1, Wells C2, Powell J3, Mar J1 and Wolvetang E1

  1. 1Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD 4072, Australia.
  2. Centre for Stem Cell Systems, MDHS, University of Melbourne, Melbourne, VIC 3010, Australia.
  3. Garvan Institute of Medical Research, Sydney, Australia.

Down syndrome (DS) is due to trisomy of HSA21. Which genes on chromosome 21 are responsible for the pronounced Alzheimer’s disease and neurocristopathy features of Down syndrome remains largely unclear. Here we use CRISPR-assisted genome manipulation to normalize the copynumber of APP or DYRK1A in DS induced pluripotent stem cells. Comparison of cellular phenotypes and transcriptomes of these isogenic euploid, DS and genome edited DS IPSC following differentiation into cortical neurons in 2D or cerebral organoid setings or analysis neural crest cells reveals important roles for APP in amyloidigenic but not tau-pathology of Alzheimers disease and the strong impact of DYRK1A dosage on neural crest cell generation, survivial and migration. We further show that these in vitro models can be used to test the efficiacy of therapeutic compounds.